A long term treatment of T cells with tumor necrosis factor alpha (TNF-alpha) paradoxically inhibits the immunologic responses to TCR/CD3 stimulation. The voltage-gated K+ channels (K-v) of T cells attracted attention as a pharmacological target for the treatment of autoimmune diseases. Here. the authors Investigated the effects of TNF-alpha on the K-v current (I-Kv) and its upregulation by CD3 in human T cells Acute treatment with TNF-alpha (10 min) temporarily decreased I-Kv in Jurkat-T cells (cells subsequently recovered after treatment >12 h) whereas CD3 stimulation for 24 h increased I-Kv amplitude more than two-fold Furthermore, chronic pretreatment with TNF-alpha almost completely blocked the I-Kv increase induced by CD3 stimulation. An immunoblot study confirmed an increase in the protein level of K-v induced by CD3 stimulation, and its inhibition by TNF-alpha pretreatment. In addition, the facilitation of I-Kv by CD3 stimulation and its inhibition by pretreatment with TNF-alpha were confirmed in freshly isolated human peripheral CD4(+) T cells. in which the voltage-dependence of I-Kv was unaffected by TNF-alpha and/or CD3 stimulation. We conclude that the inhibition of CD3-induced K-v upregulation by TNF-alpha might be associated with the paradoxical Suppression of T cell function by TNF-alpha. under conditions of chronic inflammation. (C) 2009 Elsevier Inc. All rights reserved